4 - amino - 7 - halo - 6 - pteridinecarboxylic acid esters and a process for their preparation



United States Patent 4 AMINO 7 HALO 6 PTERIDINECARBOX- YLIC ACID ESTERSAND A PROCESS FOR THEIR PREPARATION Samuel F. Sisenwine, Conshohocken,Pa., assiguor to American Home Products Corporation, New York,

N .Y., a corporation of Delaware No Drawing. Filed Feb. 1, 1968, Ser.No. 702,178

Int. Cl. C07d 57/28 US. Cl. 260251.5 3 Claims ABSTRACT OF THE DISCLOSUREThe invention concerns novel 4-amino-7-halo-6-pteridine-carboxylic acidesters and a method in which they may be used as starting materials inthe preparation of 4,7-diamino-6-pteridine-carboxamides. The formerprodnets are useful as central nervous system depressants and asintermediates to prepare the latter compounds which are useful incomparative and experimental pharmacology as diuretics.

This invention relates to a new class of pteridine compounds which areintermediates in the preparation of 4,7-diamino-6-pteridinecarboxamides. More particularly, it relates to4-amino-7-halo-6-pteridine carboxylic acid esters and a method for theirpreparation. The compounds of this invention may be represented by theformula RLKNW NTX l lHz Where X is chlorine or bromine;

R is lower alkoxy; and

R is hydrogen, Z-thienyl, 3-thienyl, lower alkyl, phenyl or phenylsubstituted with halogen, nitro, amino, hydroxy, lower alkoxy, loweralkyl or halo(lower)alkyl.

The terms lower alkyl, lower alkoxy, and the like, as used herein referto straight chain and branched groups having 1 to 6 carbon atomstherein.

The compounds of this invention may be prepared and utilized accordingto the following synthetic pro- R R and X are as defined above; and

R is hydrogen; lower alkyl; lower alkoxy(lower)alkyl,

for example methoxyalkyl; dialkylaminoalkyl, for examplediethylaminoethyl; morpholino(lower)alkyl, for example morpholinoethyl;piperidino(lower)alkyl, for example, piperidinoethyl; and loweralkylthio(lower) alkyl, for example ethylthioethyl.

3,509,150 Patented Apr. 28, 1970 ice The reaction may be carried out bycontacting an alkyl-4-amino-7-hydroxy 6 pteridinecarboxylate (II) with ahalogenation agent, e.g. phosphorus oxychloride, thionyl chloride,phosphorus tribromide, or the like, at a temperature range from about C.to about C., preferably at the reflux temperature, for a period of aboutone to about twenty-four hours, preferably two hours. Thereafter, thereaction mixture is cooled, poured into ice, stirred until all theunreacted phosphorus oxychloride, thionyl chloride, phosphorustribromide, or the like is hydrolyzed, then neutralized, for instancewith sodium bicarbonate. The product of this reaction is a4-amino-7-halo-6-pteridine carboxylic acid ester (I) which is thenrecovered by filtration and recrystallized, for instance, from a loweralkanol.

To form a 4,7-diamino-6-pteridine carboxamide (IV) which is the endproduct of the reaction, a 4-amino-7- halo-6-pteridine carboxylic acidester (I) may be mixed with an excess of an amine, such as analkoxyalkylamine, for instance, Z-methoxyethylamine, in an organicsolvent in which the reactants are substantially soluble, such as loweralkanol, for example, ethanol, isopropanol, or ethoxyethanol. The aminehas the formula R NHR where R is defined as above, and R is lower alkyl.The reaction mixture is heated at temperatures from about 50 C. to aboutC., preferably at the reflux temperature, for about one to about twelvehours, preferably about two hours. The reaction is believed to passthrough an intermediate (III) as depicted in the above reaction sequencewhich is not separated or recovered. The4,7-diamino-6-pteridinecarboxamide (IV) may be recovered by well-knowntechniques such as filtration and recrystallization from a loweralkanol, such as methanol.

The alkyl-4-amino-7-hydroxy-6-pteridine carboxylate (II) startingmaterials may be prepared as described in Osdene et al., J. MedicinalChemistry, 9,697 (1966).

As described in US. Patent, 3,254,085, issued May 31, 1966, the4,7-diamino-6-pteridinecarboxamides (IV) have been found to possessinteresting pharmaceutical properties which render them useful assynthetic medicinals, for instance as diuretics. The 4-amino 7-halo-6-idinecarboxylic acid esters (I) have utility as intermediates in thepreparation of 4,7-diamino-6-pteridinecarboxamides (IV). The4-amino-7-halo-6-pteridinecarboxylic acid esters (I) also have utilityas central nervous system depressants and as mydriatic agents.

In the pharmacological evaluation of the central nervous system activityand autonomic activity of the 4- amino-7-halo-6-pteridinecarboxylic acidesters (I) of this invention, the in vivo effects are tested as follows.The compound to be tested is administered intraperitoneally to threemice (14 to 24 grams) at each of the following doses: 400, 127, 40 and12.7 mg./kg. The animals are watched for a minimum of two hours duringwhich time signs of general stimulation (i.e., increased spontaneousmotor activity, hyperactivity on tacticle stimulation, twitching),general depression (i.e., decreased spontaneous motor activity,decreased respiration) andautonomic activity (i.e., miosis, mydriasis,diarrhea) are noted. The 4-amino 7-halo 6-pteridinecarboxylic acidesters (I) in the above procedure induce central nervous systemdepressant effects and mydriasis in mice in all the stated dose ranges.

In order more clearly to disclose the nature of the present invention,specific examples of the practice of the invention are hereinaftergiven.

EXAMPLE I This example illustrates the preparation of a 4-amino- 7-halo6-pteridinecarboxylic acid ester (1), the latter being4-amino-7-chloro-2-phenyl 6-pteridinecarboxylic acid, ethyl ester.

Ten grams of ethyl-4-amino 7-hydroxy 2-phenyl-6- pteridinecarboxylate infifty milliliters of phosphorus oxychloride (POCl are refluxed for twohours. The reaction mixture is then poured into 500 grams of ice,stirred until all the unreacted POCl is hydrolyzed, and the neutraliziedwith sodium bicarbonate (NaHCO A yellow precipitate is collected byfiltration and recrystallized from methanol. The product is4-arnino-7-chloro-2-phenyl-6-pteridinecarboxylic acid ethyl ester havinga melting point of 238 C.

Based on the formula C H N O Cl it is calculated that the elementalanalysis by weight would be 54.61 percent carbon, 3.67 percent hydrogen,21.25 percent nitrogen and 10.75 percent chlorine. The product isanalyzed, and the content is found to be 54.61 percent carbon, 3.67percent hydrogen, 21.13 percent nitrogen and 10.90 percent chlorine.This may be expressed:

Calcd for C H N O Cl (percent): C, 54.61; H, 3.67; N, 21.25; Cl, 10.75.Found (percent): C, 54.61; H, 3.67; N, 21.13; Cl, 10.90.

Following the foregoing procedure but substituting the followingstarting materials, the following products are afforded, respectively:

Starting materials Product A..- Methyl-4-amino-7-hydroxy-2-4-amino-7-chloro-2(m-ethyl-(rn-ethylphenyl)-6-pteridinephenyl)-6-pteridinecarboxyl1c carboxylateand phosphorus acid, methyl ester. oxychluride.

B-.- Hexyl-4amino-7-hydroxy-64-amiuo-7-chlero-G-pter1dmepteridinecarboxylate and carbexylic acid,hexyl ester. thionyl chloride.

C..- Ethyl-4-amino-7-hydroxy-2-(2- 4-amino-7-chloro-2-(2-thienyl)-thienyD-fi-pteridine carboxy- S-pteridinccarboxylic acid, late andthionyl chloride. ethyl ester.

D EthylA-aminoJ-hydroxyd- 4-arn1no 7-chlord2-(Ii-threnyl)-(3-thienyl)-6-pteridine carfi pteridinecarboxylic acid, boxylate andthionyl chloride. ethyl ester.

E Ethyl-4-amino-7-hydroxy-2- 4-amiu0-7-ehloro2-mcthyl-6-methyl-fi-pteridine carhoxypteridinecarhoxylic acid, late and thionylchloride. ethyl ester.

F-.. Ethyl-4-amiuo-7-hydroxy-2 4-amino-7-chloro-2-ethyl:6-

cthyl-G-pteridinecarboxylate pteridinecarboxylie acid, and thionylchloride. ethyl ester.

G Ethyl-4-amino-2butyl-7- 4-amino-2-butyl-7-chloro;6-

hydroxy-Ey-pteridine carboxypteridinecarboxyllc acid, late and thionylchloride. ethyl ester.

H Pro pyl-4-amine-7-hydr0xy-2 4-amino-7-chlore-2-toly1--tolyl-6-pteridinecarboxylate pteridinecarboxylic acid, and phosphorusoxychloride. propyl ester.

I Ethyl-4-amino-7-hydroxy-2- 4-amino-7-b route-2; (p-methoxy-(m-methoxyphenyl)-6-pteriphenyl)-6-pter1d1necarboxyhc dine carhoxylateand phosacid, ethyl ester. phorus tribromide.

J Ethyl-4-amino-7-hydroxy-2- 4-ammo-7-chloro 2-(p-ethoxy-(p-ethoxyphenyl)-6-pteridinephenyl)-6-pteridinecarboxylrc carboxylateand thionyl acid, ethyl ester. chloride. I

K Ethyl-*l-aminoJ-hydroxy-Z- 4-ammo-7-bromca2-(p-mtro-(p-nitrophenyl)-6-pteridinephenyl)-6pteridinecarhoxyl1c carhoxylate andphosphorus acid, ethyl ester. tribromide.

L-.- Ethyl-tamino-2-(o-chloro- 4-ammo-7-bromq'2(o-chlorophenyl)-7-hydroxy-fi-pteriphenyD-S-ptendmecarboxylrcdinccarboxylate and. phosacid, ethyl ester. phorus tribromide.

(p-tluorophenyD-fi-pteridine earboxylate and thionyl chloride.

Ethyl--amiuo-2-(p-bromophenyD-T-hydroxy-(i-ptern dinecarboxylate andthionyl chloride.

phenyD-G-pteridine carboxylic acid, butyl ester.

d-amino-Z-(p-hromophenyl)-7- chlor0-6-pteridinecarboxylic acid, ethylester.

Starting materials Product 0... EthylA-aminoJ-hydroxy-Z-(pqodophenyl)-6-pteridinecarboxylate and thionyl chloride.

P--- Ethyl-*t-amino-Z-(m-t rifiuoromethylphe11yD-7-hyd roxy-6-pteridiuecarboxylate and phosphorus oxychloride.

Q-.. Ethyl-tamino-Z-(m-aminophenyl)-7-hydroxy-fi-pteridinecarboxylateand phosphorus oxychloride.

R Ethyl--amino-Z-[m- (2-chl0roethyl)phenyl1-7-hydrexy-6-pteridinecarboxylate and thionyl chloride.

S Ethy1-4-amino-7-hydroxy-2 (m-hydroxyphenyl)-6-ptcri-4-amino-7-ehloro-2-(pdodophenyl)-6-pteridinecarboxylic acid, ethylester.

4-amino-7-chloro-2-(m-trifluoromethylphenyl)-6pteridinecarboxylic acid,ethyl ester.

4-amino-7-chloro-24p-aminophenyD-S-pteridinecarboxylic acid, ethylester.

4amino-7-chl0 ro-2-[p-(2-ehloroethyDphenyll-B-pteridinecarboxylic acid,ethyl ester:

4-amino-7-chloro-2-(m-hydroxyphenyl)-6-pteridiuecarboxylicdinecarboxylate and phosacid, ethyl ester. phorus oxychloride.

EXAMPLE II RZI/NWNTX where X is selected from the group consisting ofchlorine and bromine;

R is lower alkoxy; and

R is selected from the group consisting of hydrogen,

lower alkyl, Z-thienyl, 3-thienyl, and phenyl.

2. A compound as described in claim 1 which is: 4-amind7-chloro-2-pheny1-6-pteridinecarboxylic acid, ethyl ester.

3. A compound as described in claim 1 which is: 4-amino-7-bromo-2-phenyl-6-pteridinecarboxy1ic acid, ethyl ester.

References Cited UNITED STATES PATENTS 3,122,543 2/1964 Osdene 260-251.53,219,665 11/1965 Weinstock 260-251.5 3,254,085 5/1966 Osdcne 260-25 1.5

NICHOLAS S. RIZZO, Primary Examiner R. V. RUSH, Assistant Examiner US.Cl. X.R. 260-999

